PROJECT SUMMARY/ABSTRACT Between 25% and 40% of hemodialysis patients have depression, a prevalence that exceeds that of the general population by 7- to 12-fold. This already high prevalence is primed to increase. In 2018, a new Centers for Medicare & Medicaid Services (CMS) clinical quality measure mandated that dialysis facilities report depression screening rates and treatment plans to CMS annually. This heightened focus will undoubtedly increase depression diagnosis and treatment, necessitating a better understanding of anti-depressant medication safety in the hemodialysis population. Selective serotonin reuptake inhibitors (SSRIs) warrant special consideration due to their role as a first-line depression treatment and differential propensity to cause lethal cardiovascular side effects. Even though 37% of U.S. hemodialysis patients are treated with an SSRI, little is known about the comparative cardiac safety of SSRIs this vulnerable population. An undesirable property of SSRIs is their ability to delay ventricular repolarization, an effect that manifests as QT interval prolongation on an electrocardiogram (ECG). Such a conduction abnormality creates an electrophysiologic environment that favors the development of rapidly fatal arrhythmias. ECG data indicate that all six SSRIs have QT prolonging capabilities at therapeutic doses. However, citalopram and escitalopram prolong the QT interval to the greatest extent, beyond the U.S. Food and Drug Administration?s threshold of regulatory concern. Thus, treatment with citalopram or escitalopram (vs. other SSRIs) may increase sudden cardiac death risk. Hemodialysis patients may be uniquely susceptible to citalopram- and escitalopram-triggered arrythmias due to their tremendous burden of structural heart disease, thrice-weekly exposure to electrolyte shifts during dialysis treatments, and extensive use of medications that can enhance the QT prolonging effects of SSRIs. Specifically, certain hemodialysis treatment conditions known to induce QT prolongation, such as exposure to wider (vs. narrower) electrolyte blood-to-dialysate gradients, likely amplify citalopram?s and escitalopram?s pro-arrhythmic effects. While clinical trials have demonstrated that SSRIs are efficacious anti-depressants in the hemodialysis population, their small sample sizes precluded adequate safety assessments. Leveraging administrative claims data from the U.S. Renal Data System linked with detailed electronic medical record data from a large U.S. dialysis provider, we will use modern epidemiologic study designs and analytic methods to: 1) investigate the comparative 1-year risk of sudden cardiac death between hemodialysis patients initiating SSRIs with higher (citalopram or escitalopram) vs. lower (fluoxetine, fluvoxamine, paroxetine or sertraline) QT prolonging potential; and 2) investigate the near-term risk of sudden cardiac death associated with concurrent exposure to SSRIs with higher (vs. lower) QT prolonging potential and wider (vs. narrower) electrolyte blood-to-dialysate gradients during hemodialysis treatments. This study will provide clinically-actionable knowledge about the comparative cardiac safety of SSRIs in the hemodialysis population, ultimately leading to more informed SSRI prescribing.